Neurokinin ("NK") receptors such as the NK.sub.1 and the NK.sub.2 receptors are found in the central nervous system and the circulatory system and the peripheral tissues of mammals, and are involved in a variety of biological processes. Antagonists of the neurokinin receptors are, therefore, expected to be useful in the treatment or prevention of various mammalian diseases such as, for example, pulmonary disorders such as asthma, cough, bronchospasm, chronic obstructive pulmonary diseases, and airway hyperactivity; skin disorders and itch, for example, atopic dermatitis, and cutaneous wheal and flare; neurogenic inflammatory diseases such as, arthritis, migraine, nociception; CNS diseases such as anxiety, emesis, Parkinson's disease, movement disorders and psychosis; convulsive disorders, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, and eating disorders such as food intake inhibition; allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression and various disorders such as Crohn's disease. NK, receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK.sub.2 receptors have been associated with smooth muscle contraction, making NK.sub.1 and NK.sub.2 receptor antagonists especially useful in the treatment and prevention of asthma. NK.sub.1 and NK.sub.2 receptor antagonists have been reported such as, for example, in U.S. Pat. Nos. 5,798,359; 5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362; 5,688,960; 5,654,316 (all assigned to Schering-Plough Corporation, Madison, N.J.); and in "Recent Advances in Neurokinin Receptor Antagonists", by C. J. Ohnmacht Jr., et al, Annual Reports in Medicinal Chemistry, A. M. Doherty Ed., 33, 71-80 (1998).
The products of the 5-lipoxygenase ("5-LO") pathway of arachidonic acid metabolism, particularly the leukotrienes, can mediate bronchoconstriction, mucous secretion, airway mucosal edema, chemotaxis and mobilization of cells into the airway in the inflammatory process of asthma. Therefore, inhibition of 5-LO should help cure, reduce or prevent such diseases. Similarly, leukotriene ("LK") antagonists play a role in treating the multitude of symptoms associated with diseases of the respiratory tract, such as season allergic rhinitis, perennial allergic rhinitis, common colds, sinusitis and concomitant symptoms associated with allergic asthma. The symptoms of such diseases may include sneezing, itching runny nose, nasal congestion, redness of the eye, tearing, itching of the ears or palate, and coughs associated with postnasal drip. A discussion of leukotriene receptors may be found in R. Robertson, Prostaglandins, 31, 395 (1986), and a discussion of leukotriene antagonists can be found in J. Musser et al, Agents and Actions, 18, 332 (1986), J. Piwinski et al, Annual Reports in Medicinal Chemistry, 22, 73-76 (1987), and R. Bell et al, Annual Reports in Medicinal Chemistry, 32, 91 (1997).
It would be highly desirable to enhance the efficacy of the neurokinin antagonists to improve their overall efficacy, as well as to reduce or prevent the above-noted ailments by interfering with the activity of 5-LO and leukotriene receptors.